Cocaine-related overdose deaths are rapidly rising in the U.S. An effective medication for cocaine addiction is urgently needed. This proposal aims to determine whether clavulanic acid (CLAV) is effective in treating cocaine use disorder. Animal studies suggest that activation of GLT-1, the dominant astroglial glutamate transporter responsible for clearing extracellular glutamate, may provide a breakthrough approach to managing cocaine addiction. Studies in rodents demonstrate that CLAV, a non-antibiotic component of the commonly used antibiotic Augmentin, has short-term effects to a) increase GLT-1 activity, thus reducing extracellular glutamate in brain areas associated with addiction, i.e., the nucleus accumbens (NAc) and its afferent limbic region, the anterior cingulate cortex (AC), and b) inhibit the reinforcing strength of cocaine in a model of cocaine self-administration. We have concluded an inpatient study, required by the FDA, showing that the co- administration of CLAV and cocaine to volunteer non-treatment-seeking adults with cocaine use disorder is associated with decreased cocaine craving and produces no serious toxicity. Using magnetic resonance spectroscopy (MRS) at 3T, we have human pilot data demonstrating changes in brain glutamate in the AC after the first dose of CLAV, and this is maintained for 10 days of daily CLAV dosing. We now propose two human trials to assess the therapeutic effectiveness of CLAV: 1) We will determine whether CLAV maintains its therapeutic effects to reduce cocaine craving when given orally once-a-day, since CLAV has a very short half-life in the serum. Glutamate levels in the AC, measured after cessation of CLAV dosing, will be used as a biomarker to assess whether CLAV can be dosed once daily. Resting state functional connectivity will determine whether the AC increases target engagement with the NAc, and whether network deficits associated with chronic cocaine use are improved by repeated CLAV. 2) In subjects who tolerate CLAV 500 mg/day, we will determine the effects, safety and tolerability of CLAV 750 mg/day. 3) Finally, we will conduct a randomized, placebo controlled multi-site, outpatient efficacy study of CLAV in cocaine-addicted patients seeking treatment, using a formulation for once-daily dosing as determined in 2). If efficacy is confirmed (Go- No Go decision point), the project will transition to our pharmaceutical company partner, VistaGen, who will be supporting formulation development, intellectual property and regulatory strategy, as well as clinical and preclinical development during this proposal. With VistaGen, we will schedule an FDA meeting to explore breakthrough therapy status and discuss development plans leading to a New Drug Application submission.